This prospective, single-centre, single-arm, open label, phase I/II trial will assess and establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and recommended phase 2 dose (RP2D) of Radium-223 in combination with 177Lu-PSMA-I&T in patients with mCRPC.

36 men with mCRPC who have progressed on second-generation AR antagonist will be enrolled in this trial in two stages: dose escalation and a dose expansion phase over a period of 24 months.

A DLT is defined as a toxicity that prevents further administration of the trial treatment at that dose level.

Each cohort of 3 patients be assessed for DLTs in the first 6 weeks (cycle 1) of treatment and a dose for the next cohort will be determined.

Pain will be assessed using the Brief Pain Inventory - Short Form (BPI-SF). The primary endpoint for pain is the area under the curve (AUC) of the worst pain in 24h.

Pain and QoL will be assessed at baseline, 6 weeks, 3 months, 6 months, 9 months and 12 months and will be scored according to the respective manuals.

QoL will be assessed using the Functional Assessment of Cancer Therapy for Prostate Cancer (FACT-P) questionnaire. The primary endpoint for QoL is the area under the curve (AUC) of the trial outcome index (TOI).

QoL will be assessed at baseline, 6 weeks, 3 months, 6 months, 9 months and 12 months and will be scored according to the respective manuals.

Inclusion Criteria:

• Patient must be ≥ 18 years of age and must have provided written informed consent.
• Histologically or cytologically confirmed adenocarcinoma of the prostate, OR unequivocal diagnosis of metastatic prostate cancer. (i.e. involving bone or pelvic lymph nodes or para-aortic lymph nodes) with an elevated serum PSA.
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
• Patients must have progressed on ≥ 1 second-generation AR-targeted agent (e.g., enzalutamide, abiraterone, or apalutamide).
• Patients must have progressive disease for study entry. PCWG3 defines this as any one of the following:
  • PSA progression: minimum of two rising PSA values from a baseline measurement with an interval of ≥ 1 week between each measurement.
  • Soft tissue progression as per RECIST 1.1 criteria
  • Bone progression: ≥ 2 new lesions on bone scan
  • Symptomatic progression eg. Bone pain
• At least three weeks since the completion of surgery or radiotherapy prior to registration.
• Prior surgical orchiectomy or chemical castration maintained on luteinizing hormone-releasing hormone (LHRH) analogue (agonist or antagonist).
• Serum testosterone levels ≤ 1.75nmol/L (≤ 50ng/dL) within 28 days before registration.
• Significant PSMA avidity on PSMA PET/CT, defined as a minimum uptake of SUVmax 20 at a site of disease, and SUVmax >10 at sites of measurable disease >10mm (unless subject to factors explaining a lower uptake, e.g. respiratory motion, reconstruction artefact).
• ≥ 2 bone metastases must be present on bone scintigraphy which have not been previously treated with radiotherapy.
• No contraindication to treatment with a bone antiresorptive agent such as denosumab or zoledronic acid.
• Patients must have adequate bone marrow, hepatic and renal function documented within 28 days prior to registration, defined as:
  • Haemoglobin ≥ 90 g/L independent of transfusions (no red blood cell transfusion in last four weeks)
  • Absolute neutrophil count ≥ 1.5x10^9/L
  • Platelets ≥ 150 x10^9/L
  • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) except for patients with known Gilbert's syndrome, where this applies for the unconjugated bilirubin component.
  • Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN if there is no evidence of liver metastasis or ≤ 5 x ULN in the presence of liver metastases
  • Albumin ≥ 25 g/L
  • Adequate renal function: patients must have a creatinine clearance estimated of ≥ 40 mL/min using the Cockcroft Gault equation
• Sexually active patients are willing to use medically acceptable forms of barrier contraception.
• Willing to undergo biopsies, if disease is considered accessible and biopsy is feasible.
• Willing and able to comply with all study requirements, including all treatments and the timing and nature of all required assessments.

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from study entry:

• Superscan on Bone scan (WBBS) or diffuse marrow involvement on PSMA PET/CT
• Prior treatment with 223Ra or 177Lu-PSMA.
• Has not received more than one previous line of chemotherapy for the treatment of metastatic prostate cancer.
• Sites of discordant FDG-positive disease defined by minimal PSMA-expression and no uptake on WBBS (for bone metastases).
• Other malignancies within the previous 2 years other than basal cell or squamous cell carcinomas of skin or other cancers that are unlikely to recur within 24 months.
• Symptomatic brain metastases or leptomeningeal metastases.
• Patients with symptomatic or impending cord compression unless appropriately treated beforehand and clinically stable for ≥ four weeks.
• Concurrent illness, including severe infection that may jeopardise the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety.